Vitamin D deficiency triggers intrinsic apoptosis by impairing SPP1-dependent antiapoptotic signaling in chronic hematogenous osteomyelitis

Chronic hematogenous osteomyelitis (CHOM) is a common bone disease characterized by the development of sequestra after bacterial infection. Emerging evidence has shown that vitamin D (VD) deficiency raises the risk of osteomyelitis, but the underlying mechanisms remain obscure. Here, we establish a CHOM model in VD diet-deficient mice by intravenous inoculation of Staphylococcus aureus. Whole-genome microarray analyses using osteoblast cells isolated from sequestra reveal significant downregulation of SPP1 (secreted phosphoprotein 1). Molecular basis investigations show that VD sufficiency activates the VDR/RXR (VD receptor/retinoid X re-ceptor) heterodimer to recruit NCOA1 (nuclear receptor coactivator 1) and transactivate SPP1 in healthy oste-oblast cells. Secreted SPP1 binds to the cell surface molecule CD40 to activate serine/threonine-protein kinase Akt1, which then phosphorylates forkhead box O3a (FOXO3a), blocking FOXO3a-mediated transcription. By contrast, VD deficiency impairs the NCOA1-VDR/RXR-mediated overexpression of SPP1, leading to the inacti-vation of Akt1 and the accumulation of FOXO3a. FOXO3a then upregulates the expression of the apoptotic genes BAX (Bcl2-associated X-protein), BID (BH3 interacting death domain), and BIM (Bcl2-interacting mediator of cell death), to induce apoptosis. Administration of the NCOA1 inhibitor gossypol to the CHOM mice also promotes the occurrence of sequestra. VD supplementation can reactivate the SPP1-dependent antiapoptotic signaling and improve the outcomes of CHOM. Collectively, our data reveal that VD deficiency promotes bone destruction in CHOM by the removal of SPP1-dependent antiapoptotic signaling.